Parkinson's disease is a neurodegenerative disease that impairs movement and is characterized by a specific loss of dopamine neurons in a region of the midbrain called the substantia nigra (SN). Dopamine neurons in neighboring brain regions are however spared.

Previous research has shown that the SN neurons of Parkinson's disease patients contain alpha-synuclein protein and exhibit elevated levels of calcium and free intracellular dopamine (known as "cytosolic" dopamine). A study has found that a complex interaction between these factors underlies the pathology associated with Parkinson's disease. The study findings also help to explain why known risk factors do not predict Parkinson's disease in a straightforward manner.

"Although a long-standing hypothesis of neuronal neurodegeneration in Parkinson's disease postulates that elevated cytosolic dopamine underlies the selective cell death characteristic of Parkinson's disease, it has never been directly studied," explains senior study author Dr. David Sulzer. "To better understand the pathology of Parkinson's disease, we used a new electrochemical approach to measure cytosolic dopamine in neurons following various pharmacological and genetic interventions."

The researchers found that in midbrain neurons grown in culture, elevated cytosolic dopamine was toxic to neurons. Genetic and pharmacological interventions which decreased levels of cytosolic dopamine protected the neurons. The characteristic increased susceptibility of SN neurons, and not neighboring neurons, to cytosolic dopamine-related toxicity was dependent on the activity of calcium channels. Further, neurons lacking alpha-synuclein were resistant to cytosolic-dopamine-induced cell death.

The results indicate that Parkinson's disease may require multiple steps, some genetic and some environmental. "Based on our findings, we suggest that selective death of SN dopaminergic neurons responsible for the definitive motor deficits in Parkinson's disease can result from a combination of 'multiple hits' resulting from the activity of calcium channels, an increase in cytosolic dopamine and the presence of alpha-synuclein," says Dr. Sulzer. "Because interference with any of these three main factors rescued the neurons, it is likely that various strategies could be employed to prevent neuronal death in Parkinson's disease."
References:
1. David Sulzer, et al. Interplay between Cytosolic Dopamine, Calcium, and α-Synuclein Causes Selective Death of Substantia Nigra Neurons. Neuron, Volume 62, Issue 2, 218-229, 2009. doi:10.1016/j.neuron.2009.01.033.

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